CN101522619A - 非索非那定的制备方法 - Google Patents
非索非那定的制备方法 Download PDFInfo
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- CN101522619A CN101522619A CNA2007800276927A CN200780027692A CN101522619A CN 101522619 A CN101522619 A CN 101522619A CN A2007800276927 A CNA2007800276927 A CN A2007800276927A CN 200780027692 A CN200780027692 A CN 200780027692A CN 101522619 A CN101522619 A CN 101522619A
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- fexofenadine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
- C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Hydrogenated Pyridines (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Compounds Of Iron (AREA)
- Saccharide Compounds (AREA)
Abstract
描述了非索非那定的制备方法,所述方法提供用于使4-[4-[4-(羟基二苯基甲基)-1-哌啶基]-1-氧代丁基]-α,α-二甲基苯乙酸-烷基酯在水和任选的有机溶剂的混合物中在碱的存在下的水解;从而获得4-[4-[4-(羟基二苯基甲基)-1-哌啶基]-1-氧代丁基]-α,α-二甲基苯乙酸的羧酸盐,其作为羧酸盐在具有氢的碱性环境并存在合适的氢化催化剂时被还原,以得到通过中和溶液来沉淀的非索非那定的羧酸盐。
Description
非索非那定的制备方法包括:将4-[4-[4-(羟基二苯基甲基)-1-哌啶基]-1-氧代丁基]-α,α-二甲基苯乙酸烷基酯水解为4-[4-[4-(羟基二苯基甲基)-1-哌啶基]-1-氧代丁基]-α,α-二甲基苯乙酸,后者被催化氢化成非索非那定羧酸盐。
本发明涉及非索非那定的制备方法,其式如下所示:
式I
所述方法提供用于4-[4-[4-(羟基二苯基甲基)-1-哌啶基]-1-氧代丁基]-α,α-二甲基苯乙酸烷基酯在碱存在下在水和任选的有机溶剂的混合物中的水解,所述化合物也如下所示:
式II
其中R为烷基,获得4-[4-[4-(羟基二苯基甲基)-1-哌啶基]-1-氧代丁基]-α,α-二甲基苯乙酸的羧酸盐,如下所示:
式III
其中M+为羧酸盐的阳离子(换句话说,或者是用于水解的碱的阳离子),该化合物作为羧酸盐在合适催化剂的存在下在碱性环境中被氢直接被还原,得到通过中和溶液而被沉淀的非索非那定的羧酸盐。
现有技术
起始于文献报道的式II化合物的非索非那定制备方法描述了作为酮基还原优选方法的用氢化硼钠的还原作用,如在US4254129中所述。该反应可能在酯水解之前或之后进行。所提及的催化还原的方法被描述为效率较低。这些反应在有机溶液中以式II的化合物或其对应酸进行。在这些条件下,反应产率已经被证明非常低,因为完全氢解作用引起杂质形成和在苯甲基位置的一个或两个氧的丢失,该杂质构成由氢化获得的产物的约32%。
发明描述
在新方法中,式II化合物:
式II
其中R是烷基,优选C1-C4烷基,更优选甲基,溶解或悬浮在碱存在下的有机溶剂和水的混合物中,或者仅在水和碱中,在包含0℃和混合物回流温度之间的温度下通过搅拌水解。有机溶剂优选是极性溶剂,通常是质子型,优选C1-C4醇,更优选甲醇。碱优选是无机性的,例如碱金属或碱土金属的氢氧化物,更优选NaOH。
当使用时,所述有机溶剂以与水的体积比为0.25-16的范围存在;或者所述水和有机溶剂的混合物优选以是化合物II的6-7体积存在;而碱优选以式II化合物的摩尔过量使用,优选摩尔比为3-5。
式III化合物从该反应获得:
式III
其中M+是羧酸盐的阳离子,优选Na+。
将合适的金属类氢化催化剂加到体系中从而获得,优选地选自合适载体上的钯、铂或钌(优选披钯碳),并且在0℃与溶剂沸点之间的温度在1-100bar、优选1-10bar压力范围下被氢化。
式I的非索非那定,通过氢化反应获得:
式I
其然后通过用酸优选乙酸中和溶液中存在的碱来沉淀。
以下实施例纯粹为阐述性而并非限制本发明。
实施例1
在配有机械搅拌器的四颈瓶中,装入100g 4-[4-[4-(羟基二苯基甲基)-1-哌啶基]-1-氧代丁基]-α,α-二甲基苯乙酸甲酯、600ml甲醇和60ml 30%氢氧化钠。回流加热混合物并在搅拌下维持约5小时。当酯完全水解后,将10g 5%的披钯碳装入反应器并在50℃和6bar压力下氢化,直到苯甲酮完全转化为相的醇。一旦反应完成,滤去催化剂并通过用乙酸调节pH至5-8来沉淀非索非那定。将所获得的固体过滤并在65℃真空干燥。
平均得到85g HPLC纯度>99%的粗非索非那定。氢化作用最适温度:35-45℃;沉淀的pH为5-6。
实施例2
在配有机械搅拌器的四颈瓶中,装入100g 4-[4-[4-(羟基二苯基甲基)-1-哌啶基]-1-氧代丁基]-α,α-二甲基苯乙酸甲酯、600ml水、150ml异丙醇和73ml 30%氢氧化钠。回流加热混合物并在搅拌下维持约5小时。当酯完全水解后,将10g 5%的披钯碳装入反应器并且在50℃和6bar压力下氢化,直到苯甲酮完全转化为相应的醇。一旦反应完成,滤去催化剂并通过用乙酸调节pH至5-8来沉淀非索非那定。将所获得的固体过滤并在65℃真空干燥。
平均得到85g HPLC纯度>99%的粗非索非那定。氢化作用最适温度:35-45℃;沉淀pH为5-6。
实施例3
在配有机械搅拌器的四颈瓶中,装入100g 4-[4-[4-(羟基二苯基甲基)-1-哌啶基]-1-氧代丁基]-α,α-二甲基苯乙酸甲酯、600ml甲醇和60ml 30%氢氧化钠。回流加热混合物并在搅拌下维持约5小时。当酯完全水解后,将10g 5%的披钯碳装入反应器并且在50℃和10bar压力下氢化,直到苯甲酮完全转化为相应的醇。一旦反应完成,滤去催化剂并通过用乙酸调节pH至5-8来沉淀非索非那定。将所获得的固体过滤并在65℃真空干燥。
平均得到85g HPLC纯度>99%的粗非索非那定。氢化作用最适温度:35-45℃;沉淀pH为5-6。
实施例4
在配有机械搅拌器的四颈瓶中,装入100g 4-[4-[4-(羟基二苯基甲基)-1-哌啶基]-1-氧代丁基]-α,α-二甲基苯乙酸甲酯和600ml甲醇。当酯完全溶解后,将10g 5%披钯碳装入反应器并且在50℃和6bar压力下氢化,直到苯甲酮完全转化为对应的醇。一旦反应完成,滤去催化剂,加入60ml 30%氢氧化钠,回流加热混合物并在搅拌下维持约5小时直至酯完全水解。通过用乙酸调节pH至5-8来沉淀非索非那定。将所获得的固体过滤并在65℃真空干燥。
得到55g HPLC纯度约60%的粗非索非那定和通过分子量计算少于一个氧(one less oxygen)且A%等于32的杂质。
Claims (15)
2.权利要求1的方法,其中R是C1-C4烷基,优选甲基。
3.权利要求1的方法,其中所述水解在有机溶剂和水的混合物或仅在水中进行。
4.权利要求3的方法,其中所述有机溶剂是极性有机溶剂,优选质子溶剂。
5.权利要求3的方法,其中所述有机溶剂是C1-C4醇,优选甲醇。
6.权利要求3的方法,其中所述有机溶剂以与水的体积比为0.25-16的范围存在。
7.权利要求3的方法,其中所述水和有机溶剂的混合物以是所述化合物的6-7体积存在。
8.权利要求1的方法,其中所述碱以式II化合物的摩尔过量使用,优选摩尔比为3-5。
9.权利要求1的方法,其中所述碱是碱金属或碱土金属的氢氧化物,优选NaOH。
10.权利要求1的方法,其中M+是Na+。
11.权利要求1的方法,其中所述氢化作用在氢化催化剂存在下进行。
12.权利要求11的方法,其中所述催化剂选自钯、铂和钌。
13.权利要求11的方法,其中所述催化剂为披钯碳。
14.权利要求11的方法,其中所述氢化作用在0℃至溶剂沸点之间的温度下进行。
15.权利要求11的方法,其中所述氢化作用在1-100bar、优选1-10bar压力下进行。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IT001492A ITMI20061492A1 (it) | 2006-07-27 | 2006-07-27 | Processo per la preparazione di fexofenadina. |
ITMI2006A001492 | 2006-07-27 | ||
PCT/IT2007/000525 WO2008012858A1 (en) | 2006-07-27 | 2007-07-25 | Process for preparing fexofenadine |
Publications (2)
Publication Number | Publication Date |
---|---|
CN101522619A true CN101522619A (zh) | 2009-09-02 |
CN101522619B CN101522619B (zh) | 2012-01-04 |
Family
ID=38777957
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN2007800276927A Expired - Fee Related CN101522619B (zh) | 2006-07-27 | 2007-07-25 | 非索非那定的制备方法 |
Country Status (10)
Country | Link |
---|---|
US (1) | US9403770B2 (zh) |
EP (1) | EP2046743B1 (zh) |
JP (1) | JP5196501B2 (zh) |
KR (1) | KR101413877B1 (zh) |
CN (1) | CN101522619B (zh) |
AT (1) | ATE488502T1 (zh) |
DE (1) | DE602007010638D1 (zh) |
ES (1) | ES2356269T3 (zh) |
IT (1) | ITMI20061492A1 (zh) |
WO (1) | WO2008012858A1 (zh) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN106699559A (zh) * | 2015-11-12 | 2017-05-24 | 浙江九洲药业股份有限公司 | 一种洛索洛芬钠的制备工艺 |
CN107782804A (zh) * | 2016-08-25 | 2018-03-09 | 人福普克药业(武汉)有限公司 | 检测盐酸非索非那定样品中有关物质的方法 |
Family Cites Families (14)
Publication number | Priority date | Publication date | Assignee | Title |
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US4254130A (en) * | 1979-04-10 | 1981-03-03 | Richardson-Merrell Inc. | Piperidine derivatives |
US4254129A (en) * | 1979-04-10 | 1981-03-03 | Richardson-Merrell Inc. | Piperidine derivatives |
US5136070A (en) * | 1991-12-23 | 1992-08-04 | Dow Corning Corporation | Sodium borohydride catalyzed disproportionation of cycloorganosilanes |
HU226561B1 (en) * | 1992-04-10 | 2009-04-28 | Merrell Dow Pharma | Process for preparation 4-diphenylmethyl piperidine derivatives and the novel intermediates thereof |
DK1026147T3 (da) * | 1993-06-24 | 2004-03-22 | Albany Molecular Res Inc | Forbindelser, der er anvendelige som mellemprodukter i fremstillingen af piperidinderivater |
US20020007068A1 (en) * | 1999-07-16 | 2002-01-17 | D'ambra Thomas E. | Piperidine derivatives and process for their production |
EP2261207A1 (en) * | 1993-06-25 | 2010-12-15 | Aventisub II Inc. | Intermediates for the preparation of antihistaminic 4-diphenylmethyl/diphenylmethoxy piperidine derivatives |
US6153754A (en) * | 1995-12-21 | 2000-11-28 | Albany Molecular Research, Inc. | Process for production of piperidine derivatives |
US6201124B1 (en) * | 1995-12-21 | 2001-03-13 | Albany Molecular Research, Inc. | Process for production of piperidine derivatives |
US6689898B2 (en) * | 1998-07-02 | 2004-02-10 | Aventis Pharmaceuticals Inc. | Antihistaminic piperidine derivatives and intermediates for the preparation thereof |
ITRM20010260A1 (it) * | 2001-05-17 | 2002-11-18 | Dinamite Dipharma S P A In For | Processo per la preparazione della fexofenadina o acido 4 1-idrossi-4-4- (idrossidifenilmetil)-1-piperidinil|-butil|-alfa,alfa-dimetilbenz |
US6743941B2 (en) * | 2001-06-15 | 2004-06-01 | Aventis Pharma Deutschland Gmbh | Process for the production of piperidine derivatives |
ITMI20041143A1 (it) * | 2004-06-08 | 2004-09-08 | Dipharma Spa | Polimorfi di fexofenadina e procedimento per la loro preparazione |
EP1685106A2 (en) * | 2004-09-28 | 2006-08-02 | Teva Pharmaceutical Industries, Inc. | Fexofendadine crystal form and processes for its preparation thereof |
-
2006
- 2006-07-27 IT IT001492A patent/ITMI20061492A1/it unknown
-
2007
- 2007-07-25 US US12/374,539 patent/US9403770B2/en not_active Expired - Fee Related
- 2007-07-25 AT AT07805737T patent/ATE488502T1/de not_active IP Right Cessation
- 2007-07-25 JP JP2009521422A patent/JP5196501B2/ja not_active Expired - Fee Related
- 2007-07-25 CN CN2007800276927A patent/CN101522619B/zh not_active Expired - Fee Related
- 2007-07-25 DE DE602007010638T patent/DE602007010638D1/de active Active
- 2007-07-25 EP EP07805737A patent/EP2046743B1/en not_active Not-in-force
- 2007-07-25 ES ES07805737T patent/ES2356269T3/es active Active
- 2007-07-25 KR KR1020097001409A patent/KR101413877B1/ko not_active IP Right Cessation
- 2007-07-25 WO PCT/IT2007/000525 patent/WO2008012858A1/en active Application Filing
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN106699559A (zh) * | 2015-11-12 | 2017-05-24 | 浙江九洲药业股份有限公司 | 一种洛索洛芬钠的制备工艺 |
CN107782804A (zh) * | 2016-08-25 | 2018-03-09 | 人福普克药业(武汉)有限公司 | 检测盐酸非索非那定样品中有关物质的方法 |
Also Published As
Publication number | Publication date |
---|---|
US9403770B2 (en) | 2016-08-02 |
EP2046743A1 (en) | 2009-04-15 |
EP2046743B1 (en) | 2010-11-17 |
ES2356269T3 (es) | 2011-04-06 |
ATE488502T1 (de) | 2010-12-15 |
CN101522619B (zh) | 2012-01-04 |
JP5196501B2 (ja) | 2013-05-15 |
DE602007010638D1 (de) | 2010-12-30 |
ITMI20061492A1 (it) | 2008-01-28 |
KR20090034905A (ko) | 2009-04-08 |
KR101413877B1 (ko) | 2014-06-30 |
WO2008012858A1 (en) | 2008-01-31 |
US20110190504A1 (en) | 2011-08-04 |
JP2009544691A (ja) | 2009-12-17 |
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